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Abstract

70

Linkage studies in spontaneously hypertensive rats (SHR) have implicated a host of different DNA sequence variants in the genetic control of blood pressure (BP) and a variety of other cardiovascular phenotypes. However, direct proof that any of these gene variants represents a true quantitative trait locus (QTL) regulating BP or any other complex trait is lacking. To directly test the identity of putative QTL in the SHR model, we have: 1) developed transgenic techniques for rescuing mutant alleles directly on the SHR background and 2) used these techniques to determine whether a gene encoding a fatty acid transporter (Cd36) truly represents a QTL that can influence the clustering of multiple cardiovascular risk factors in spontaneous hypertension. Towards these ends, we have successfully derived multiple transgenic strains of SHR (SHR-TG strains) that express the wild type allele for Cd36 on an SHR background harboring the deletion variant of Cd36 (SHR control). In these strains, low level expression of wild type Cd36 on the mutant SHR background ameliorated glucose intolerance (e.g., area under the GTT curve = 713±21 in the SHR-TG19 strain vs. 954±45 mmol/L/2hr in the SHR control strain, p<.001), insulin resistance (e.g., insulin stimulated glucose uptake in muscle = 355±104 in the SHR-TG19 strain vs. 135±13 nmol/g/2 hrs in the SHR control strain, p<.01), and dyslipidemia (e.g., fatty acid levels = 276±27 in the SHR-TG19 strain vs. 389±42 μmol/L in the SHR control strain, p<.05). Similar results were observed in the SHR-TG10 strain. In addition, in the SHR-TG19 strain, transgenic expression of wild type Cd36 in the kidney was associated with significant reductions in BP (p<.005 by radiotelemetry). These findings: 1) demonstrate that transgenic SHR can be derived to directly test the identity of putative QTL for complex cardiovascular traits; 2) establish that defective Cd36 is a bona fide QTL that can influence the clustering of multiple cardiovascular risk factors in spontaneous hypertension, and 3)should motivate further studies on the role of Cd36 in the regulation of BP, renal function, and the pathogenesis of hypertension.